| Title: |
Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis |
| Authors: |
Rhodes, Christopher J.; Batai, Ken; Bleda, Marta; Haimel, Matthias; Southgate, Laura; Germain, Marine; Pauciulo, Michael W.; Hadinnapola, Charaka; Aman, Jurjan; Girerd, Barbara; Arora, Amit; Knight, Jo; Hanscombe, Ken B.; Karnes, Jason H.; Kaakinen, Marika; Gall, Henning; Ulrich, Anna; Harbaum, Lars; Cebola, Ines; Ferrer, Jorge; Lutz, Katie; Swietlik, Emilia M.; Ahmad, Ferhaan; Amouyel, Philippe; Archer, Stephen L.; Argula, Rahul; Austin, Eric D.; Badesch, David; Bakshi, Sahil; Barnett, Christopher; Benza, Raymond; Bhatt, Nitin; Bogaard, Harm J.; Burger, Charles D.; Chakinala, Murali; Church, Colin; Coghlan, John G.; Condliffe, Robin; Corris, Paul A.; Danesino, Cesare; Debette, Stephanie; Elliott, C. Gregory; Elwing, Jean; Eyries, Melanie; Fortin, Terry; Franke, Andre; Frantz, Robert P.; Frost, Adaani; Garcia, Joe G.N.; Ghio, Stefano; Ghofrani, Hossein-Ardeschir; Gibbs, J. Simon R.; Harley, John; He, Hua; Hill, Nicholas S.; Hirsch, Russel; Houweling, Arjan C.; Howard, Luke S.; Ivy, Dunbar; Kiely, David G.; Klinger, James; Kovacs, Gabor; Lahm, Tim; Laudes, Matthias; Machado, Rajiv D.; Ross, Robert V. MacKenzie; Marsolo, Keith; Martin, Lisa J.; Moledina, Shahin; Montani, David; Nathan, Steven D.; Newnham, Michael; Olschewski, Andrea; Olschewski, Horst; Oudiz, Ronald J.; Ouwehand, Willem H.; Peacock, Andrew J.; Pepke-Zaba, Joanna; Rehman, Zia; Robbins, Ivan; Roden, Dan M.; Rosenzweig, Erika B.; Saydain, Ghulam; Scelsi, Laura; Schilz, Robert; Seeger, Werner; Shaffer, Christian M.; Simms, Robert W.; Simon, Marc; Sitbon, Olivier; Suntharalingam, Jay; Tang, Haiyang; Tchourbanov, Alexander Y.; Thenappan, Thenappan; Torres, Fernando; Toshner, Mark R.; Treacy, Carmen M.; Noordegraaf, Anton Vonk; Waisfisz, Quinten; Walsworth, Anna K.; Walter, Robert E.; Wharton, John; White, R. James; Wilt, Jeffrey; Wort, Stephen J.; Yung, Delphine; Lawrie, Allan; Humbert, Marc; Soubrier, Florent; Tregouet, David-Alexandre; Prokopenko, Inga; Kittles, Richard; Graf, Stefan; Nichols, William C.; Trembath, Richard C.; Desai, Ankit A.; Morrell, Nicholas W.; Wilkins, Martin R.; Adlard, Julian; Ahmed, Munaza; Aitman, Tim; Alachkar, Hana; Allsup, David; Almeida-King, Jeff; Ancliff, Philip; Antrobus, Richard; Armstrong, Ruth; Arno, Gavin; Ashford, Sofie; Astle, William; Attwood, Anthony; Babbs, Chris; Bakchoul, Tamam; Bariana, Tadbir; Barwell, Julian; Bennett, David; Bentley, David; Bierzynska, Agnieszka; Biss, Tina; Bogaard, Harm; Bourne, Christian; Boyce, Sara; Bradley, John; Breen, Gerome; Brennan, Paul; Brewer, Carole; Brown, Matthew; Browning, Michael; Buchan, Rachel; Buckland, Matthew; Bueser, Teofila; Burns, Siobhan; Burren, Oliver; Calleja, Paul; Carr-White, Gerald; Carss, Keren; Casey, Ruth; Caulfield, Mark; Chambers, John; Chambers, Jennifer; Cheng, Floria; Chinnery, Patrick F.; Christian, Martin; Brod, Naomi Clements; Coghlan, Gerry; Colby, Elizabeth; Cole, Trevor; Collins, Janine; Collins, Peter; Colombo, Camilla; Cook, Stuart; Cook, Terry; Cooper, Nichola; Corris, Paul; Crisp-Hihn, Abigail; Curry, Nicola; Daniels, Matthew; Daugherty, Louise; Davis, John; Deevi, Sri V.V.; Dent, Timothy; Dewhurst, Eleanor; Dixon, Peter; Downes, Kate; Drazyk, Anna; Drewe, Elizabeth; Dutt, Tina; Edgar, David; Edwards, Karen; Egner, William; Erber, Wendy; Erwood, Marie; Estiu, Maria C.; Evans, Gillian; Evans, Dafydd Gareth; Everington, Tamara; Eyries, Mlanie; Favier, Remi; Fletcher, Debra; Fox, James; Frary, Amy; French, Courtney; Freson, Kathleen; Frontini, Mattia; Gale, Daniel; Geoghegan, Claire; Gerighty, Terry; Gibbs, Simon; Gilmour, Kimberley; Goddard, Sarah; Gomez, Keith; Gordins, Pavels; Gosal, David; Grassi, Luigi; Greene, Daniel; Greenhalgh, Lynn; Greinacher, Andreas; Gresele, Paolo; Griffiths, Philip; Grigoriadou, Sofia; Grocock, Russell; Grozeva, Detelina; Hackett, Scott; Hague, William; Hall, Matthew; Hanson, Helen; Harkness, Kirsty; Harper, Andrew; Harris, Claire; Hart, Daniel; Hassan, Ahamad; Hayman, Grant; Henderson, Alex; Hoffmann, Jonathan; Horvath, Rita; Houweling, Arjan; Howard, Luke; Hu, Fengyuan; Hudson, Gavin; Hughes, Joseph; Huissoon, Aarnoud; Humphray, Sean; Hunter, Sarah; Hurles, Matthew; Izatt, Louise; James, Roger; Johnson, Sally; Jolles, Stephen; Jolley, Jennifer; Jurkute, Neringa; Kasanicki, Mary; Kazkaz, Hanadi; Kazmi, Rashid; Kelleher, Peter; Kiely, David; Kingston, Nathalie; Klima, Robert; Kostadima, Myrto; Koziell, Ania; Kreuzhuber, Roman; Kuijpers, Taco; Kumar, Ajith; Kumararatne, Dinakantha; Kurian, Manju; Laffan, Michael; Lalloo, Fiona; Lambert, Michele; Allen, Hana Lango; Layton, Mark; Lentaigne, Claire; Levine, Adam; Linger, Rachel; Longhurst, Hilary; Louka, Eleni; Ross, Robert MacKenzie; Madan, Bella; Maher, Eamonn; Maimaris, Jesmeen; Mangles, Sarah; Mapeta, Rutendo; Marchbank, Kevin; Marks, Stephen; Markus, Hugh S.; Marschall, Hanns-Ulrich; Marshall, Andrew; Martin, Jennifer; Mathias, Mary; Matthews, Emma; Maxwell, Heather; McAlinden, Paul; McCarthy, Mark; Meacham, Stuart; Mead, Adam; Megy, Karyn; Mehta, Sarju; Michaelides, Michel; Millar, Carolyn; Moore, Tony; Morrell, Nicholas; Mozere, Monika; Muir, Keith; Mumford, Andrew; O'Sullivan, Jennifer; Obaji, Samya; Okoli, Steven; Ong, Kai Ren; Ormondroyd, Elizabeth; Ouwehand, Willem; Papadia, Sofia; Park, Soo-Mi; Parry, David; Paterson, Joan; Peacock, Andrew; Peden, John; Peerlinck, Kathelijne; Penkett, Christopher; Petersen, Romina; Pyle, Angela; Rankin, Stuart; Rao, Anupama; Raymond, F. Lucy; Rayner-Matthews, Paula; Rees, Christine; Rendon, Augusto; Renton, Tara; Rice, Andrew; Richardson, Sylvia; Richter, Alex; Roberts, Irene; Roughley, Catherine; Roy, Noemi; Sadeghi-Alavijeh, Omid; Saleem, Moin; Samani, Nilesh; Sanchis-Juan, Alba; Sargur, Ravishankar; Satchell, Simon; Savic, Sinisa; Schulman, Sol; Scully, Marie; Searle, Claire; Sewell, Carrock; Seyres, Denis; Shapiro, Susie; Sharmardina, Olga; Shtoyerman, Rakefet; Sibson, Keith; Side, Lucy; Simeoni, Ilenia; Simpson, Michael; Sivapalaratnam, Suthesh; Skytte, Anne-Bine; Smith, Katherine; Smith, Kenneth G.C.; Snape, Katie; Staines, Simon; Staples, Emily; Stark, Hannah; Stephens, Jonathan; Stirrups, Kathleen; Stock, Sophie; Swietlik, Emilia; Tait, R. Campbell; Talks, Kate; Tan, Rhea; Thaventhiran, James; Themistocleous, Andreas; Thomas, Moira; Thomson, Kate; Thrasher, Adrian; Thys, Chantal; Tischkowitz, Marc; Titterton, Catherine; Toh, Cheng-Hock; Toshner, Mark; Traylor, Matthew; Treacy, Carmen; Trembath, Richard; Tuna, Salih; Turek, Wojciech; Turro, Ernest; Vale, Tom; Van Geet, Chris; Van Zuydam, Natalie; Vazquez-Lopez, Marta; Von Ziegenweidt, Julie; Waisfisz, Quintin; Walker, Suellen; Ware, James; Watkins, Hugh; Watt, Christopher; Webster, Andrew; Wei, Wei; Welch, Steven; Wessels, Julie; Westbury, Sarah; Westwood, John-Paul; Whitehorn, Deborah; Whitworth, James; Williamson, Catherine; Wong, Edwin; Wood, Nicholas; Wood, Yvette; Woods, Geoff; Woodward, Emma; Wort, Stephen; Worth, Austen; Yates, Katherine; Yong, Patrick; Young, Tim; Yu, Ping; Yu-Wai-Man, Patrick; Theuer, Alison; Malur, Anagha; Williams, Ann; Dotson, Anne; Warden, Ashley; Harrington, Brandy; Vang, Brenda; Ziemak, Caitlin; Casanova, Nancy; Caskey, Elizabeth; MacDonald, Catherine; Rowley, Courtney; Larimore, Daniel; Brady, Daniela; Tomer, David; Davis, Anne; Broach, Debra; Devereux, Jane; Lovato, Ellen; Stratton, Eric; Turk, Erin; Jackson, Esperanza; Paciotti, Gina; Peichel, Gretchen; Birru, Hellina; del Junco, Holly; Ingledue, Rebecca; Bruno, Jackie; Drake, Jan; Marks, Jennifer; Pisarcik, Jessica; Spears, Jill; Santiago, Joseph; DeMartino, Jordyn; Beckmann, Joy; Palmer, Julia; Visnaw, Karen; Kennedy, Karla; Lewis, Karlise; Miller-Reed, Kathleen; Hannon, Kelly; McClain, Kimberly; Dillon, Laura; Olanipekun, Lekan; Mendibles, Lillian; Hawke, Lindsey; Brody, Linnea; Durst, Louise; Andrews, Mary; Allahua, Melissa; Stratoberdha, Melissa; Lemma, Merte; Cope, Molly; Franzo, Mya; Feliz, Natalia; Hawkes, Nicholas; Norwood, Tracy; Wilson, Opal; Palmisciano, Amy; Gruhlke, Peggy; Correa, Priscilla; Blake, Randy; Karnekar, Reema; Do, Robyn; Rohwer, Kristal; Ahmed, Sara; Schiltz, Kimberly; Scovel, Page; Cordell, Shannon; Heuerman, Sharon; Ahmad, Shazzra; Szuberla, Sylwia; Roads, Tammy; Iem, Thoeun; Mcgaha, Traci; Urban, Tracy; Aston, Valerie; Ayesh, Waleed; Light, Allison; Arkon, Abby; Tavlarides, Andrea; Anderson, Audrey; Bindu, John; Boekwig, Deedre; Singleton, Donna; Abrea, Inna; Lee, Jennifer; Ormiston, Mark; Whitman, Renesa; Holy, Royanne; Almeida-Peters, Sisama; Igenoza, Tosin; Farber, Hap; Reponen, Auvo; Barve, Mukta; Gygi, Amber; Winslow, Clayborne |
| Source: |
ISSN:2213-2600 ; ISSN:2213-2619 ; Lancet Respiratory Medicine, vol. 7 (3), (227-238. |
| Publisher Information: |
Elsevier |
| Publication Year: |
2019 |
| Subject Terms: |
Science & Technology; Life Sciences & Biomedicine; Critical Care Medicine; Respiratory System; General & Internal Medicine; ENDODERM FORMATION; SOX17; SUSCEPTIBILITY; DISEASE; ALPHA; Female; Genetic Predisposition to Disease; Genetic Variation; Genome-Wide Association Study; Genotyping Techniques; HLA-DP alpha-Chains; HLA-DP beta-Chains; Humans; Male; Middle Aged; Polymorphism; Single Nucleotide; Pulmonary Arterial Hypertension; Risk Assessment; SOXF Transcription Factors; Signal Transduction; Survival Analysis; UK NIHR BioResource Rare Diseases Consortium; UK PAH Cohort Study Consortium; US PAH Biobank Consortium |
| Description: |
BACKGROUND: Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes. METHODS: We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses. FINDINGS: A locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55-2·08], p=5·13 × 10-15) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42-1·71], p=7·65 × 10-20) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25-1·48], p=1·69 × 10-12; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients ... |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
https://lirias.kuleuven.be/handle/123456789/635678; https://pubmed.ncbi.nlm.nih.gov/30527956 |
| DOI: |
10.1016/S2213-2600(18)30409-0 |
| Availability: |
https://lirias.kuleuven.be/handle/123456789/635678; https://lirias.kuleuven.be/retrieve/510ed71f-3a84-41bd-99fb-e4078a90bc35; https://doi.org/10.1016/S2213-2600(18)30409-0; https://pubmed.ncbi.nlm.nih.gov/30527956 |
| Rights: |
info:eu-repo/semantics/openAccess ; public |
| Accession Number: |
edsbas.50824CC9 |
| Database: |
BASE |